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Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling
Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MB(Group3)) have the poorest prognosis. Here we identify a previous...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357694/ https://www.ncbi.nlm.nih.gov/pubmed/34302498 http://dx.doi.org/10.1007/s00401-021-02347-7 |
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author | Nazio, Francesca Po, Agnese Abballe, Luana Ballabio, Claudio Diomedi Camassei, Francesca Bordi, Matteo Camera, Antonio Caruso, Simona Caruana, Ignazio Pezzullo, Marco Ferraina, Caterina Milletti, Giacomo Gianesello, Matteo Reddel, Sofia De Luca, Carmen Dolores Ceglie, Donatella Marinelli, Sara Campello, Silvia Papaleo, Elena Miele, Evelina Cacchione, Antonella Carai, Andrea Vinci, Maria Velardi, Enrico De Angelis, Biagio Tiberi, Luca Quintarelli, Concetta Mastronuzzi, Angela Ferretti, Elisabetta Locatelli, Franco Cecconi, Francesco |
author_facet | Nazio, Francesca Po, Agnese Abballe, Luana Ballabio, Claudio Diomedi Camassei, Francesca Bordi, Matteo Camera, Antonio Caruso, Simona Caruana, Ignazio Pezzullo, Marco Ferraina, Caterina Milletti, Giacomo Gianesello, Matteo Reddel, Sofia De Luca, Carmen Dolores Ceglie, Donatella Marinelli, Sara Campello, Silvia Papaleo, Elena Miele, Evelina Cacchione, Antonella Carai, Andrea Vinci, Maria Velardi, Enrico De Angelis, Biagio Tiberi, Luca Quintarelli, Concetta Mastronuzzi, Angela Ferretti, Elisabetta Locatelli, Franco Cecconi, Francesco |
author_sort | Nazio, Francesca |
collection | PubMed |
description | Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MB(Group3)) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MB(Group3) stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MB(Group3) stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MB(Group3) outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MB(Group3). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-021-02347-7. |
format | Online Article Text |
id | pubmed-8357694 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-83576942021-08-30 Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling Nazio, Francesca Po, Agnese Abballe, Luana Ballabio, Claudio Diomedi Camassei, Francesca Bordi, Matteo Camera, Antonio Caruso, Simona Caruana, Ignazio Pezzullo, Marco Ferraina, Caterina Milletti, Giacomo Gianesello, Matteo Reddel, Sofia De Luca, Carmen Dolores Ceglie, Donatella Marinelli, Sara Campello, Silvia Papaleo, Elena Miele, Evelina Cacchione, Antonella Carai, Andrea Vinci, Maria Velardi, Enrico De Angelis, Biagio Tiberi, Luca Quintarelli, Concetta Mastronuzzi, Angela Ferretti, Elisabetta Locatelli, Franco Cecconi, Francesco Acta Neuropathol Original Paper Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MB(Group3)) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MB(Group3) stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MB(Group3) stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MB(Group3) outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MB(Group3). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-021-02347-7. Springer Berlin Heidelberg 2021-07-24 2021 /pmc/articles/PMC8357694/ /pubmed/34302498 http://dx.doi.org/10.1007/s00401-021-02347-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Paper Nazio, Francesca Po, Agnese Abballe, Luana Ballabio, Claudio Diomedi Camassei, Francesca Bordi, Matteo Camera, Antonio Caruso, Simona Caruana, Ignazio Pezzullo, Marco Ferraina, Caterina Milletti, Giacomo Gianesello, Matteo Reddel, Sofia De Luca, Carmen Dolores Ceglie, Donatella Marinelli, Sara Campello, Silvia Papaleo, Elena Miele, Evelina Cacchione, Antonella Carai, Andrea Vinci, Maria Velardi, Enrico De Angelis, Biagio Tiberi, Luca Quintarelli, Concetta Mastronuzzi, Angela Ferretti, Elisabetta Locatelli, Franco Cecconi, Francesco Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling |
title | Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling |
title_full | Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling |
title_fullStr | Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling |
title_full_unstemmed | Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling |
title_short | Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling |
title_sort | targeting cancer stem cells in medulloblastoma by inhibiting ambra1 dual function in autophagy and stat3 signalling |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357694/ https://www.ncbi.nlm.nih.gov/pubmed/34302498 http://dx.doi.org/10.1007/s00401-021-02347-7 |
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